Dr Hermione Lyall

Dr Hermione Lyall
Imperial College Healthcare NHS Trust, London
RCOG, London
2015 - Aiming for Zero Transmission
HIV Exposed Uninfected Infants - HEUs
are there any problems?
Hermione Lyall
Imperial Healthcare
NHS Trust
27.11.15
Acknowledgements:
Chrissie Jones, Andrew Prendergast, Pat Tookey,
Claire Townsend, Claire Thorne, Graham Taylor,
Gareth Tudor-Williams Marc Lallement, Catherine Peckham
The “foetal-infant” environment & HIV
Resource Rich
Resource Poor
Foetal environment
Post natal environment
Genetics
Genetics
Nutrition
Environment
Immune function
Nutrition
Immune activation
Breast / formula
HIV Viral Load
Immune function
ART drugs
Immune
activation
Foetal
Other drugs
Maternal microbiome
Stress?
Other infections
Maternal well being
Prematurity
Poverty / Orphanhood
Smoking
etc
HIV un-exposed un-infected
HUU
etc
HIV exposed un-infected
HEU
HIV exposed infected
HEI
Effects of HIV / Drug exposure?
Resource Rich Resource Poor
Mortality / Survival
Haematology
Brain
Cardiovascular
Skin
Infections
Gut
Immunology
Growth
Bones
Carcinogenesis
Endocrine
OTHERS??
Mitochondria
Mortality among HEU African infants
mortality up to 3 years, but not at 5-8 years
Filteau 2009 Trop Med Int Health
Infectious morbidity in HEU infants – in Africa
Low birth weight & low birth Neutrophils ↑ morbidity & mortality
Hospitalisation for infection ↑↑ 20% in HEUs
↑↑ severe infections, more complications
↑↑ LRTI (> in mothers with advanced HIV)
↑↑ Pneumococcal infections
↑↑ oral thrush
↑↑ TB (inc congenital TB)
OIs – PJP, CMV
↑↑ Post-operative infections & mortality (SA)
↑↑ diarrhoea, is probably related more to mode of feeding than
HIV exposure.
Cotrimoxazole ↓morbidity & mortality in HEU infants
Shapiro, J Inf Dis 2007; Koyanagi, PIDJ, 2011; McNally Lancet 2007; Kourtis AIDS. 2013
USA - HEU - morbidity & mortality
during the first 2 yrs of life
Women & Infants Transmission Study (WITS).
1990-2001 evaluation at birth, 1, 2, 4, 6, 9, 12, 18, 24 months
Growth, hospitalization, clinical disease (HEU 955, HEI 163)
Over 11 yrs - morbidity & mortality during the first 24 months of
life decreased substantially for HEU infants.
HEU: ↑ short stature, poor weight gain & wasting compared to
the general population.
Two or more changes in caretaker growth deficiency
Fetal exposure to tobacco height abnormalities.
Anemia common associated with ZDV prophylaxis.
Paul et al, Pediatr Infect Dis J. 2005
Infectious morbidity in HEU infants – Europe
French Perinatal Cohort – n = 7638, 2002-10 (only HEU)
↑↑ hospitalisation for infection in first year of life (9.3%)
699 serious infections, 159 bacterial
Bacterial infection - ↑ with ↓ maternal CD4 (esp encapsulated)
Viral infection – no effect of maternal CD4
Clement Taron-Brocard et al. Clin Infect Dis. 2014;59:1332-1345
Infectious morbidity in HEU infants – Belgium
Belgian single centre cohort, n= 537
Severe infections in 1st year of life – 16.8 /100 HUE years
Compared to general population: Strep pneumo ↑↑ 4x, Group B Strep ↑↑ 13x
Born1994-2006, no ARVs
Born1994-2006, ARVs
Born 1985-1994, no ARVs
Risk factors for severe
infection in this cohort:
Prematurity ↑↑ 21x neonatal period
↑↑ 3x post-neonatal
Born in post ARV era
↑↑ with /without ART
Adler et al PLoS One 2015
Group B Strep infection ↑↑ in HEU
Africa – South Africa
antibodies to GBS:
↓ in pregnant women
with HIV
↓ in new-born HEU
infants (trans-placental)
↓ in HEU infants at 16
weeks of age
Increased risk of EOS
and LOS disease
Le Doare K, Vaccine. 2015
Europe – Belgium
HEU
HUU
1.55%
0.08%
6/322
16/20158
Late onset infection
5/6
2/16
HEU had more severe
disease.
most were leukopaenic
at presentation.
Epalza C, Pediatrics. 2010
Increased risk of mortality from invasive
pneumococcal disease in HEU infants aged <1
year in South Africa, 2009-2013.
Invasive pneumococcal disease, n = 2099 cases, 2009 / 2013
92% known HIV exposure status, 86% known outcomes
Exposure
HEI
HEU
HUU
IPD rate / 100,000
2009
2013
654
272
88
33
28
18
Case Fatality
overall < 6mths of age
34%
29%
37%*
25%
32%
*rel risk 1.76x
Need to prioritise HEU for pneumococcal immunisation
von Mollendorf, Clin Infect Dis. 2015
Congenital CMV and HEU infants
Canadian study n = 1255 – 2.2% cCMV
↑↑ in mothers with ↓↓ CD4 counts, born earlier, lower birth weight
Gantt S, J Med Virol. 2015
South African study n = 748 – 2.9% cCMV (96% of women on ART)
↑↑ 2.9x in mothers ↓↓ CD4 <200
No significant effect of: maternal age, type of ART, length of ART, gest age /
birth weight.
Manicklal S, Clin Infect Dis. 2014
French Perinatal Cohort n = 4797 – overall 2.3% cCMV
HEI
10.3% HEU 2.2%
HEU
1997- 1998
3.5%
2003 - 2004 1.2%
Logistical regression analysis – significant factors:
Delivery period, maternal age, maternal CD4 < 200, time of starting ART.
Guibert G, Clin Infect Dis. 2009
Postnatal CMV infection in HEU ↑ if mother not on ART, or CD4<200
Frederick et al Clin Infect Dis. 2012
Immune abnormalities in HIVexposed, uninfected infants
CD4 CD8
Cytokines Immune activation Naïve T cell Memory T cell Reviewed in Afran 2013, Clin Exp Imm
Immune abnormalities in HIVexposed, uninfected infants
Afran 2013
Immunology in HEU
European Collaborative Study n= 1663 HEU,
followed from birth – for at least 8 yrs
Standard protocol to measure TLC, CD4 & CD8 cell counts.
Ethnicity
black children - ↓TLC, CD4, CD8 cell counts than white
black children - ↑ TLC, CD4 & CD8 lymphopaenic counts
ART exposure
ART - ↓ TLC & CD4 cell counts in 1st year of life
ART - ↓ CD8 cell counts until at least 8 years of age
ART duration & intensity - associated with TLC levels
Bunders et al, AIDS. 2005
Placental transfer of maternal antibody
– reduced in HEU
HEU infants are more vulnerable to infections
Timely infant vaccination
Consider immunisation in pregnancy to protect in early life
Jones, 2011,
Le Doare, Vaccine, 2014
De Moraes-Pinto, 1996 & 1998
Cumberland, 2007
Scott, 2007
Responses to Vaccination in HEU and HUU
HEU
HUU
Ref
Diphtheria
Similar
Similar
Simani, AIDS, 2014
Tetanus
Similar
Similar
Jones, JAMA, 2011
Similar
Similar
Reikie, CVI, 2013
Similar
Similar
Simani, AIDS, 2014
Pertussis
(PT & FHA)
Higher
Lower
Jones, JAMA, 2011
Higher
Lower
Reikie, CVI, 2013
PT
Higher
lower
Simani, AIDS, 2014
FHA
Similar
Similar
Simani, AIDS, 2014
Hib
(PRP)
Similar
Similar
Jones, JAMA, 2011
Similar
Similar
Reikie, CVI, 2013
Similar
Similar
Simani, AIDS, 2014
Similar
Similar
Simani, AIDS, 2014
HEU
HUU
Ref
Lower
Higher
Simani, AIDS, 2014
Higher
proportion
of nonresponders
and good
responders
Lower
proportion
of noresponder
s or good
responder
s
Abramczuk, CVI,
2011
Similar
Similar
Reikie, CVI, 2013
Pneumococcu
s
Higher
Lower
Jones, JAMA, 2011
Serotypespecific
Similar
Similar
Madhi, JID, 2010
OPA
Similar
(except
serotype
19F)
Similar
Madhi, JID, 2010
Measles 1st
dose
Higher
Lower
Simani, AIDS, 2013
Similar
Similar
Reikie, CVI, 2013
2nd
Lower
Higher
Simani, AIDS, 2013
Higher in exposed
Similar in exposed &
unexposed
Lower in exposed
PRP SBA
HBsAg
Higher in exposed
Similar in exposed &
unexposed
Lower in exposed
Measles
dose
Responses to Vaccination in HEU and HUU
HEU
Higher in exposed
Similar in exposed &
unexposed
Lower in exposed
HUU
Ref
BCG at birth
Altered
patterns
BCG at 6
weeks
Similar
Similar
Jones, AIDS, 2014
BCG at birth
Similar
Similar
Mansoor, JID, 2009
BCG at birth
Similar
Similar
Elliott, 2010, Vaccine
BCG
Similar @
6/52
Similar @
6/52
Kidzeru, 2014, AIDS
Higher @
14/52
Lower @
14/52
Lower
polyfunc
Higher
polyfunc
Higher
CD4
Lower
CD4
Lower GD
Higher GD
BCG
Van Rie, 2008, CVI
Mazzola, 2011, AIDS
In general, HEU infants mount a robust antibody responses to vaccines
and are likely to be equally protected as HUU
Intra-uterine Growth in European HUE
European Collaborative Study - weight, height, & OFC, n=1912
Birth weight / OFC
Born at term or before 34 weeks no difference if exposed to
mono/ no ART or cART
Born at 34 -36 weeks, increased weight if on cART
Gestational age and maternal illicit drug use were strongly
associated with growth, effect of cART was marginal.
Hankin et al, J Acquir Immune Defic Syndr. 2005
USA similar growth & body composition - HEU
& HUU.
HEU weigh less at birth slightly ↑ growth in the
first 2 years of life. HEU had less subcutaneous fat
and decreasing mid-upper arm circumference over
time when compared with US standards.
Neri et al, J Pediatr. 2013
Growth & Development in Zambian HEU / HUU
111 HEU, 279 HUU, aged 6-12 years, assessed Anthropometry
Health questionnaire & clinical exam
BP, Hb, HbA1c, glucose, cholest, CRP
Most recent school report
• HEU smaller and less fat than HUU
– difference became non-significant when adjusted for socio-demographic variables
• HEU ↑ minor illness and ↑ meds prescribed
• No difference between HEU and HUU in biochemical markers
• HEU lower maths grades
– difference maintained when adjusted for socio-demographic variables
Nicholson et al, BMC Pediatr. 2015
Growth, Bones & Tenofovir
Infant growth outcomes after maternal tenofovir use during pregnancy.
IMPAACT P1025 (infants born 2002-2011)
n=2025 at birth (31% TDF exposed); n=1496 at 6 mths (31% TDF exposed)
By most measures, in utero exposure to tenofovir did not significantly predict
infant birth weight or growth through 6 months of age.
Ransom et al, J Acquir Immune Defic Syndr. 2013
New born meconium TDF concentrations
↑ meconium TFV concentrations greater gestational ages (ρ = 0.29, P =
0.03) and lower maternal HIV RNA before delivery (ρ = -0.29, P = 0.04).
Meconium TFV concentrations were not associated with infant weight,
length (n = 58) or bone mineral content (n = 49).
Pediatric HIVAIDS Cohort Study (PHACS), PIDJ 2015
Haematology - Neutrophils
ECS - Levels and patterns of neutrophil counts
for first 8 years of life. HEI n=156 HEU n=1533
HIV-infection: after 4 months of age,
neutrophil counts were consistently and substantially lower.
Advanced HIV disease & ARV ↓ ↓ neutrophil count.
Ethnicity: black children ↓ lower counts than white across the
age range
HEU: male gender, & ARV exposure were associated with
reduced neutrophil count until at least 8 years of age.
clinical relevance of reduced levels of neutrophils?
European Collaborative Study.AIDS. 2004
USA Women & Infants
Transmission Study
(WITS)
HEU n=1820 ARV-exposed
HEU n= 351 ARV-unexposed
0 – 24 months of age
0-2 mths ART-exposed:
↓ Hb, Neut, TLC, CD4+
6-24 mths ART-exposed:
↓ platelet, TLC, CD4+
↓ CD8+
cART compared to mono-ART:
↓ Neut, TLC, CD8+ at 0-2 mths
↓ CD8+ at 6-24 mths
Small differences – is there a
clinical significance?
Susan E. Pacheco et al. J Infect Dis. 2006;194:1089-1097
HEU Mitochondrial Morbidity & Exposure
to Nucleoside Analogues?
The French Perinatal Cohort Stephane Blanche et al
* Crude rate in French cohort
Observed back ground rate
French Cohort
MITOCHONDROPATHY
Significant evidence for:
“Possible”
“Established”*
ART exposed
2644
28
14
7
2002
3 / 1000
1 / 10 000
Un-exposed
1748
1
0
0
USA retrospective review of perinatal exposure to ART in PACTS Study.
No NRTI exposed HEU died of mitochondrial disorders (n=118 deaths < 5 years)
No living HUEs had symptoms of mitochondrial dysfunction (n=1951).
Bulterys et al, Ann N Y Acad Sci. 2000
“MITOC” study commissioned by EMA results still awaited$$
Transient lactic acidemia in HEU infants
exposed to perinatal ART
Plasma lactate > normal,at least once in 35 / 38 (92%) infants
Reached levels > 5 mmol/l in 10 (26%) infants
78 /117 (68%) lactates were elevated (11 > 5 mmol/l)
No infants received ART beyond 6 weeks
Elevated lactates persisted up to age 6 months
2 infants had symptoms consistent with lactic academia
No association between the infant peak lactate and the type or
duration of ART during pregnancy
Alimenti et al, Pediatr Infect Dis J. 2003
In utero NRTI exposure & possible
mitochondrial dysfunction in HEU.
PACTG 219/219C n=1037 HEU born 1991-2002
Possible cases with signs of MD according to “Enquête
Périnatale Française” criteria were identified retrospectively
Cases (n = 20) significantly more likely to be male and born in
earlier years than non-cases (n = 1017)
Overall no association between in NRTI exposure & MD
When adjusted for year of birth the odds of first exposure in the
third trimester to 3TC (OR, 10.57; 95% CI, 1.93-75.61) and ZDV/3TC
(OR, 9.84; 95% CI, 1.77-71.68) higher among cases than non-cases.
Unable to control for confounding by maternal viral load or
psychoactive drug use.
Brogly et al, AIDS. 2007
Some evidence of small changes in mDNA in cases.
Brogly et al, AIDS Res Hum Retroviruses. 2011
Antiretroviral exposure and lymphocyte mtDNA content
among HEU
controls
birth
2 years
5 years
mtDNA - stored PBMCs (Primagen Retina Mitox assay)
411 HUU and 213 HEU (+/- in-utero and neonatal ARV)
mtDNA ↓ in HEU compared to HUU
mtDNA ↑ in HEU+ART compared to HEU-ART
By 5 years of age:
mtDNA ↑ to normal levels in HEU+ART, but remain lower in HEU-ART
Aldrovandi et al, Pediatrics. 2009
Cardiac effects of in-utero exposure to
antiretroviral therapy in HEU children.
Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring for
ART Toxicities study.
No significant differences in echocardiographic Z-scores
between 417 HEU and 98 HUU, aged 2-7 years.
Subclinical differences in left ventricular structure and function
with 1st trimester exposure to cART.
lower stress-velocity Z-scores
lower LV dimension Z-scores
higher mean LV posterior wall thickness
lower mean LV wall stress Z-scores
Lipshultz et al, AIDS. 2015
Brain - cognitive & academic outcomes
USA Pediatric HIVAIDS Cohort Study HEU 5-13 yrs.
Test
number
% ART exposure
WPPSI-IIIs
350
84%
WASI
337
64%
WIAT-II-A
415
67%
Cognitive Performance: No association with ART regime or class
Same factors as associated with lower performance in general pop applied in
this cohort: prematurity; SGA; maternal alcohol; lower maternal IQ etc.
Nozyce, Pediatr Infect Dis J. 2014
USA PACT 219/219C n = 1840, born 1993-2006, 92% ART exposed
Bayley Scales of Infant Development (BSID) at 2yrs of age
No effect of ART exposure on BSID scores
LBW infants had higher scores if ART exposed
17% of mothers used illicit drugs, no effect on BSID scores
Williams et al,Pediatrics. 2010
Cognitive & Academic outcomes
in HEU compared to HUU
Zambia – B+ era, ART exposure (inutero & BF)
Capute Full-Scale Develop quotient HEU n=97 HUU n=103
No significant difference in performance Ngoma et al, AIDS. 2014
Thailand & Cambodia – HEU n = 160, HUU n = 167
Beery Visual Motor Integration (VMI) test, Color Trails, Perdue Pegboard, and Child
Behavior Checklist (CBCL), Thai children (n = 202) also completed the Wechsler
Intelligence Scale (IQ) and Stanford-Binet II memory tests.
Adjusted for caregiver education, parent as caregiver, income, age, ethnicity.
Slightly lower scores on verbal IQ, full-scale IQ, & Binet Bead
Memory in HEU, uncertain significance.
No differences in performance IQ, other Binet memory
domains, Color Trail, Perdue Pegboard, Beery VMI, or CBCL
test scores.
Kerr et al, AIDS Care. 2014
ART & Language Outcomes in
HEU Infants.
Risk for late language emergence after in utero ART exposure in HEU
infants.
1129 language assessments were conducted among 792 1- and 2-year-old
children. In utero cARV exposure showed little association with LLE, except
for higher risk of language delay observed in 1-year-old infants with
atazanavir exposure.
Pediatric HIVAIDS Cohort Study (PHACS), Pediatr Infect Dis J. 2013
Meconium ART concentrations
↑ meconium atazanavir concentrations were protective against
developmental language delays at 1 year, suggesting the importance of
fetal ATV detoxification into meconium. This supports ATV exposure safety
for infant language development.
Pediatric HIVAIDS Cohort Study (PHACS), Pediatr Infect Dis J. 2015
Malignancy? – no data yet
NSHPC Data linkage - flagging
•
•
•
•
Office for National Statistics
Births, deaths, cancer registration, emigration
Flagging studies provide event notification
UK born infants born to infected women being flagged
(no names – complex procedure)
• Numbers for babies
• Other data linkage possibilities
• Ethics and consent issues – public health considerations
Specific drug effects - Kaletra newborn toxicity
Kaletra liquid - 42% ethanol, & 15% propylene glycol
Neonatal ⇓ liver metabolism – CP3A / alcohol dehydrogenase
FDA adverse events reporting system (AERS) <2yrs
10 cases of severe toxicity, 8 prems (28-35 wks)
7 Cardiac toxicity (cardiac failure, AV block, bradycardia)
5 acute renal failure (⇑ K common); 3 CNS effects
1 death (assoc with an over dose), rest improved on d/c Kal
Rx started on day 1 of life in 7/10
NB – no denominator data;
FDA safety alert 8.3.11 – avoid Kaletra in <14 day old infants
unless no alternatives – monitor organ function closely
Association of prenatal & postnatal exposure to lopinavirritonavir & adrenal dysfunction among uninfected
infants of HIV-infected mothers
JAMA. 2011 Jul 6;306(1):70-8. ANRS French Perinatal Cohort Study Group
French cohort
All term newborns on lopinavir-ritonavir were asymptomatic
3 premature infants life-threatening symptoms compatible adrenal in-sufficiency (hyponatremia, hyperkalemia with, in
1 case, cardiogenic shock)
All symptoms resolved off lopinavir-ritonavir treatment
• Kaletra
• Controls (ZDV)
7 / 50 ⇑ 17OHP levels – 14%
0 / 108 ⇑ 17OHP levels
• French Guthrie Card National rate ⇑ 17OHP levels – 0.03%
Lopinavir - Ritonavir
cytochrome inhibition
⇓ cytochrome /enzyme CYP21
⇑ 17- OHP ⇑ DNEA
adrenal insufficiency
Is this only due to Kaletra or is it a PI class effect?
PROMISE MTCT Through Age 14 Days
Significantly Lower in Triple ARV Arms
1.8%
25 infections/
1,326
9 infections/
1,710
Difference in MTCT Risk (Repeated Confidence Interval):
-1.28% (95% CI -2.11%, -0.44%)
PROMISE summary of 1077BF/FF Antepartum
Component Infant Safety Results
• There were no significant differences in infant
signs/symptoms and lab AEs by study arm.
• There were 60 early infant deaths by 14 days;
including 28 deaths in version 3.0.
• In V 3.0, there was a significantly lower risk of
infant death for ZDV/3TC vs TDF/FTC:
– 0.6%(2/346) vs. 4.4% (15/341), p=0.001
The difference was primarily seen in deaths among
infants less than <34 weeks gestation –why?
39
Effects of HIV / ART exposure?
Resource Rich Resource Poor
Mortality / Survival
With maternal ART
Without maternal ART
⇓ Infant HIV Tx
⇓ HEU infections
⇑ Prematurity
⇑ Drug toxicities
⇑ Infant HIV Tx
⇑ Immune dysfunction
⇑ HEU infections
⇑ Orphans / poverty
Well designed – large long term follow up studies
in resource poor settings
are essential to assess these effects
NSHPC
Children enrolled in CHART
n = 307 children enrolled (born 1996-2003)
No health or developmental problem
At least one “usual” problem
107 (35%)
179 (58%)
e.g. childhood infections, asthma, gastroenteritis
Specific health / developmental problem
Congenital abnormalities (7)
Posterior urethral valves
Cleft lip & palate
Hydrocephalus (aqueduct stenosis)
Spina bifida & hydrocephalus
Ovarian cyst
Pulmonary stenosis
Talipes
21 (7%)
Others (14)
Febrile seizure (5)
Sickle cell disease (4)
Cerebral palsy 2° to prematurity
Intraventricular haemorrhage (prem)
Head injury & 2° developmental delay
Atopy with seizure
Autism
Follow up of uninfected children exposed to ART:
UK CHART study 2002-05
Investigated logistics of long-term follow up of uninfected HIV-exposed
children
Explored whether serious adverse outcomes associated with exposure to
ART in fetal/early life were apparent in early childhood
Incorporated NSHPC data on ART exposure, delivery etc.
CHART data on health/development in early childhood
Prevalence of abnormal outcomes within UK norms, but numbers small
and duration of follow up limited
Comprehensive long-term clinic-based follow up not feasible in UK
alternative approaches required, e.g. secure data linkage protocols
NSHPC
Hankin CD et al. AIDS Care 2009, 19(1):482-486
Elimination of infant HIV A dream in 1994 Reality in 2015
access to HIV tests & effective ART
There are consequences for HIV &
ART exposed uninfected infants –
its our job to minimise these effects
and optimise outcomes –
How to do long term surveillance?
www.bhiva.org